Project Summary Globally, gastric cancer is a major health burden and remains one of the leading causes of cancer-related death. As is true of several cancer types, gastric cancer development is often preceded by the emergence of preneoplastic lesions. In gastric carcinogenesis, Helicobacter pylori-induced oxyntic atrophy causes chronic inflammation and histopathologic changes that lead to metaplasia and then cancer in the gastric mucosa. Identifying the events that promote metaplasia development in the stomach remains a priority, as identification of any of these factors could lead to better surveillance methods and therapies. Our previous work in mouse models of acute oxyntic atrophy have shown that metaplasia in the stomach develops in the setting of a type II immune response, including production of type II cytokines, eosinophil infiltration, and alternatively activated macrophages. In particular, we have shown that mice lacking Interleukin-13 (IL-13) fail to develop metaplasia following oxyntic atrophy. It is clear that IL-13 plays an important role in the development of metaplasia, however the source of IL-13 remains unknown. Type II innate lymphoid cells (ILC2s) have recently emerged as important effector cells capable of producing robust levels of IL-13. ILC2s are a main contributor of IL-13 in the gastrointestinal tract. I hypothesize that ILC2s are required for the development of metaplasia in the stomach because they produce IL-13, which promotes chief cell transdifferentiation. To address this hypothesis, I will pursue three specific aims. First, I will characterize tissue resident ILC2s found in the normal and metaplastic gastric mucosa using single cell RNA sequencing and primary culture systems. Second, I will determine the effects of depleting ILC2s in mouse models of acute oxyntic atrophy and metaplasia. Finally, I will determine if IL-13 directly promotes chief cell transdifferentiation using a previously characterized conditionally- immortalized chief cell culture system. Overall, these investigations could link the pathological progression of metaplasia in the stomach to other type II mediated diseases and provide preclinical insights that may lead to novel approaches to alter metaplasia development.